Pharmaceutical compositions that are orally administered for release of an active ingredient upon ingestion are usually comprised of a tablet or capsule consisting of an inert carrier material in which one or more active drugs has been incorporated. The carrier material may comprise a majority of the tablet or capsule weight and mass and serves to both protect the active ingredient during its shelf life as well as controlling its release rate during ingestion. Different excipients provide sustained, long lasting release while others may be formulated to immediately release the drug in the stomach. High potency drugs often achieve their therapeutic effects at very low doses so that a very deminimus amount of the active ingredient actually makes up the respective capsule or tablet composition. Nevertheless, uniform distribution of the drug throughout the carrier matrix is essential for proper release.
Active pharmaceutical agents may be dissolved in a solvent and then mixed with the carrier material. The solvent is then removed by drying, usually using heat, reduced pressure or a combination of both whereby the drug then becomes entrapped within or deposited on the carrier matrix. Water soluble drugs can simply be dissolved in water but water insoluble drugs must be dissolved in an organic solvent such as alcohol and the like which creates additional problems in manufacturing. Not only are the organic solvents highly volatile and thereby present a safety and health risk to those preparing the pharmaceutical compositions, but their use is also problematical from the point of drug reactivity and the need to remove all of the solvent from the composition so as to not leave any residue which may be detrimental to the pharmaceutical composition.
The removal of organic solvents in their near entirety from the pharmaceutical composition is generally a necessary step in the formulation of most pharmaceuticals. Any residue not only becomes an unwanted contaminant but may, during storage, adversely affect the active drugs potency or activity. Resins such a polyvinylpyrrolidone have been used to remove alcohol from aqueous solutions of a compound of interest, see U.S. Pat. No. 4,359,593 to Feldman, and techniques such as aeration, reduced atmospheric pressure and distillation are obviously all well known techniques in the art to achieve the same ends.
U.S. Pat. No. 4,684,519 to Barabas discloses the preparation of pharmaceutical compositions wherein the active complex is dissolved in ethanol which is then mixed with water to create an alcohol-water azeotrope. The solvent is removed by heat distillation and the active product dried. U.S. Patent Nos. 4,305,502 and 4,371,516 both to Gregory et. al disclose the preparation of an active pharmaceutical composition wherein the active is incorporated in an inert carrier by dissolving the active in a solvent, usually water, which is then removed from the composition using sublimation.
U.S. Pat. No. 4,74,597 to Buxton et. al. takes this process another step by first dissolving a water-soluble carrier material in water which is removed by sublimation so as to create an interstitial network of channels within the carrier matrix. The active, which is dissolved in a second non-aqueous solvent, is added to the carrier material and deposited in the interstitial network of channels by slowly evaporating the solvent at room temperature.
It has been found that many water insoluble drugs that necessitate their dissolution in an organic solvent are adversely effected by techniques that remove the solvent, particularly when the solvent employed reaches low levels in the drug/carrier matrix. It is an object of the present invention to provide a process that allows for the removal of substantially all the organic solvent from a drug/excipient blend, or at least to within a negligible limit, without adversely affecting the potency or stability of the actives involved. It is a further object of the present invention to uniformly disperse potent active drugs throughout a relatively large excipient/carrier blend resulting in a final product with little to no organic solvent residue. It is a further object of the present invention to provide pharmaceutical compositions of highly potent drugs in a carrier matrix that is both stable and contaminant free.